Process for the preparation of azabicyclic derivatives

ABSTRACT

A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R 1  represents (a) in which r represents an integer of 2 to 4, s represents 1 or 2 and t represents 0 or 1; R 2  is a group OR 4 , where R 4  is C 1-4  alkyl, C 2-4  alkenyl or C 2-4  alkynyl or a group OCOR 5  where R 5  is hydrogen or R 4  ; and R 3  is CN; said process comprising reacting a compound of formula (II) wherein R 1  &#39; is R 1  or a group convertible thereto, and R 3  &#39; is an electron withdrawing group, with a source of nitrous acid, and thereafter converting the resulting ═NOH group to ═NR 2  wherein R 2  is as defined in formula (I), converting R 1  &#39; and R 3  &#39; when other than R 1  and R 3  to R 1  and R 3 , and thereafter optionally forming a pharmaceutically acceptable salt.

This is a 371 of PCT/EP95/01757 filed May 9, 1995.

This invention relates to a process for the preparation of compoundshaving pharmaceutical activity.

EP-A-0392803 (Beecham Group p.l.c.) discloses certain azabicycliccompounds which enhance acetylcholine function via an action atmuscarinic receptors within the central nervous system.

These compounds are therefore of potential use in the treatment and/orprophylaxis of dementia in mammals. Various preparative methods are alsodisclosed.

WO93/17018 and WO 92/03433 disclose certain routes to intermediatesuseful in the preparation of certain compounds disclosed inEP-A-0392803.

We have now developed an improved process for the preparation of oneclass of the compounds disclosed in EP-A-0392803.

The present invention provides a process for the preparation of acompound of formula (I) or a pharmaceutically acceptable salt thereof:##STR2## wherein R₁ represents ##STR3## r represents an integer of 2 to4, s represents 1 or 2 and t represents 0 or 1;

R₂ is a group OR₄, where R₄ is C₁₋₄ alkyl, C₂₋₄ alkenyl or C₂₋₄ alkynylor a group OCOR₅ where R₅ is hydrogen or R₄ ; and

R₃ is CN;

said process comprising reacting a compound of formula (II): ##STR4##wherein R₁ ' is R₁ or a group convertible thereto, and R₃ ' is anelectron withdrawing group, with a source of nitrous acid and thereafterconverting the resulting ═NOH group to ═NR₂ wherein R₂ is as defined informula (I), converting R₁ ' and R₃ ' when other than R₁ and R₃ to R₁and R₃, and thereafter optionally forming a pharmaceutically acceptablesalt.

Compounds of formula (I) are capable of existing in a number ofstereoisomeric forms including geometric isomers such as E and Z and,for certain compounds, enantiomers. The different stereoisomeric formsmay be separated one from the other by the usual methods.

If desired, the compounds of formula (I) can be formed into acidaddition salts with acids, such as the conventional pharmaceuticallyacceptable acids, for example hydrochloric, hydrobromic, phosphoric,acetic, fumaric, salicylic, citric, lactic, mandelic, tararic, oxalicand methanesulphonic.

The term pharmaceutically acceptable salt encompasses solvates andhydrates. Thus where compounds of formula (I) or pharmaceuticallyacceptable salts thereof form solvates or hydrates, these also form anaspect of the invention.

Preferred combinations of (r,s,t) include (2,2,0), (2,1,1), (3,1,1),(2,1,0) and (3,1,0), most preferably (2,2,0).

The groups R₄ and R₅ in R₂ are preferably selected from methyl, ethyl,allyl and propargyl. Suitable values for R₂ include methoxy, ethoxy,allyloxy, propargyloxy and acetoxy, preferably methoxy.

Examples of suitable electron withdrawing groups include CN, CO₂ R andCON(R)₂ in which each R is independently H, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl C₁₋₄ alkyl or aryl C₁₋₄alkyl, wherein aryl groups are selected from optionally substitutedphenyl and naphthyl. Suitable examples of substituents on phenyl andnaphthyl include one or more, for example 1 to 3, substituents selectedfrom halo, hydroxy, C₁₋₄ alkoxy and C₁₋₄ alkyl. R₃ ' is preferably CN.

The compound of formula (II) may be provided in the form of an esterhydrolysed to the free acid prior to reaction with the source of nitrousacid.

The reaction of the compound of formula (II) with the source of nitrousacid, for example an alkali metal nitrite such as sodium nitrite may becarried out in aqueous acid such as hydrochloric acid for example at 0°C. to 50° C.

After basification, the reaction results in a compound of formula (III):##STR5## When R₁ ' is R₁ where (r, s, t) is (2, 2, 0) and R₃ ' is CN,the Z isomer of the compound of formula (III) may be crystallised outfrom the reaction mixture in the zwitterionic form. Compounds of formula(III) in zwitterionic form are novel and as such form part of theinvention.

The ═NOH group of the oxime of formula (III) may be converted to ═NR₂ byconventional routes, for example compounds where R₂ is OCOR₅ can be madeby acylation with an acylating agent such as an acyl halide, for exampleacetyl chloride. Compounds where R₂ is OR₄ can be made by alkylationwith an alkylating agent such as methyl tosylate (methyl p-toluenesulphonate) or an alkyl halide, for example methyl iodide. Thealkylation is preferably carried out at a temperature of -20° C.-40° C.,more preferably 0° C.-40° C., for example 18° C.-36° C., most preferablybelow 35° C., and is preferably preceded by treatment of oxime offormula (III) with base such as potassium t-butoxide.

R₃ ' groups other than CN may be converted thereto conventionally, forexample by conversion, if necessary, to the primary amide followed bydehydration.

Examples of R₁ ' groups other than R₁ include suitable azacyclicprecursors which may be cyclised as described in, for example, EP0392803.

The different stereoisomeric forms of compounds of formula (I) may beseparated one from the other by the usual methods, for examplechromatographic methods or during treatment of the compound of formula(I) or earlier intermediates such as of formula (III) with chiralresolving agents. Enantiomers may be separated using chiral resolvingagents such as L-(+)-tartaric acid, D-(+)-malic acid, gulonic acidderivatives such as 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid,camphorsulphonic acid, dibenzoyl tartaric acid, mandelic acid and(S)-(+)- and (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, orchiral chromatography. For resolution of the compound of formula (I),where (r, s, t) is (2, 2, 0), R₂ is methoxy and R₃ is CN,2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid is particularlypreferred and can achieve separation of the E/Z geometric isomers. Theresolution process forms a further aspect of the invention. The unwantedenantiomer obtained from the separation may be racemised by treatmentwith a strong base such as potassium t-butoxide and the resultingmixture of enantiomers and geometric isomers separated again to furnishthe required isomer. For resolution of the compound of formula (III)where R₁ ' is R₁, (r,s,t) is (2,2,0) and R₃ ' is CN, L-(+)-tartaric andD-(+)-malic acids are particularly preferred and the resolution processforms a further aspect of the invention.

Accordingly, the invention therefore provides a process for resolvingR,S!-α-(methoximino)-α-(l-azabicyclo 2.2.2!oct-3-yl)acetonitrile,optionally obtained by the process of the invention, which comprisestreating the racemic compound with2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid, separating theresolved R-(Z) isomer as the crystalline gulonate salt, optionallyracemising the mother liquors with strong base and obtaining a furthercrop of resolved R-(Z) isomer gulonate salt by repeating the treatmentprocess, and thereafter converting the resolved R-(Z) isomer into thefree base or a pharmaceutically acceptable salt.

The invention further provides a process for resolving racemicR,S-(Z)!-α-(oximino)-α-(1-azabicyclo 2.2.2!oct-3-yl)acetonitrile whichcomprises treating the racemic compound, optionally obtained by theprocess of the invention, with L-(+)-tartaric or D-(+)-malic acid,separating the resolved R-(Z) isomer as the crystalline tartrate ormalate salt and thereafter converting the salt to the free base.

In the preparation of the desired R-(Z) isomer of the compound offormula (I), where (r,s,t) is (2,2,0), R₂ is methoxy and R₃ is CN, it ispreferred to obtain the Z isomer of the intermediate compound of formula(III) as described above. The Z isomer of the oxime of formula (III) maybe resolved into the desired R enantiomer before methylation of the ═NOHgroup. It has been found that base treatment of the resolved oxime doesnot result in unwanted racemisation of the oxime and that methylationproceeds smoothly to the required R-(Z) isomer of the final compound.This methylation process forms another aspect of the invention.

The invention therefore provides a process for preparingR-(Z)!-α-(methoxyimino)-α-(1-azabicyclo 2.2.2!oct-3-yl)acetonitrile or apharmaceutically acceptable salt thereof which comprises treatingR-(Z)!-α-(oximino)-α-(1-azabicyclo 2.2.2!oct-3-yl)acetonitrile,optionally obtained by the resolution process of the invention, withbase, methylating the product and thereafter optionally forming apharmaceutically acceptable salt.

Methylation may result in some alkylation on the oxime nitrogen to givea nitrone. Hydrolysis of the reaction mixture after methylation withaqueous base such as K₂ CO₃ at elevated temperature for example 50°-60°C. results in removal of the nitrone side product.

Higher enantiomeric purity can be achieved, if required, byrecrystallisation of the chiral salt from a suitable solvent such aswater (for compounds of formula (III)) or ethyl acetate/methanol (forcompounds of formula (I)).

The invention also provides a process for preparing a compound offormula (III) which process comprises reacting a compound of formula(II) with a source of nitrous acid such as an alkali metal nitrite andthereafter converting R₁ ' and R₃ ' when other than R₁ and R₃ to R₁ andR₃ and thereafter optionally forming a salt.

Compounds of formula (II) can be prepared from corresponding compoundsof formula (IV) or esters thereof: ##STR6## by hydrogenation accordingto standard procedures optionally followed by ester hydrolysis andconversion of R₁ ' and R₃ ' to R₁ or CN respectively.

The reduction of compounds of formula (IV) and their esters ispreferably carried out by treating a solution of a compound of formula(IV) or ester with hydrogen under atmospheric or elevated pressure, inthe presence of a precious metal catalyst such as Palladium on carbon.The resulting compound of formula (II) may be isolated or alternativelythe reaction product may be used directly in the reaction with thesource of nitrous acid.

Compounds of formulae (II) and (IV) are novel and as such form part ofthe invention.

Compounds of formula (IV) may be prepared by reacting a compound offormula (V): ##STR7## with a compound R₃ ' CH₂ CO₂ H or the ester,optionally followed by conversion of R₁ ' and/or R₃ ' to R₁ or CNrespectively.

The reaction of a compound of formula (V) may be carried out in aqueousbase, such as sodium hydroxide at moderate temperatures, for exampleambient to 50° C.

Where the R₃ ' group is a carboxy derivative such as an alkoxycarbonylgroup, it may be converted to a cyano group by conventional methods asdescribed above, but preferably before hydrogenation or the reactionwith alkali metal nitrite.

However, as stated above, R₃ ' is preferably cyano and no conversion isnecessary.

Intermediates of formula (V) are known compounds (e.g. as described inThill et al., J. Org. Chem., 1968, 33, 4376) or may be preparedanalogously.

The compounds of formula (I) are useful in therapy as described inEP-0392803.

The following Examples illustrate the invention.

EXAMPLE 1 Preparation of R,S-(Z)!-α-(oximino)-α-(1-azabicyclo2.2.2!oct-3-yl)acetonitrile

Method A

Stage 1 Preparation of 1-azabicyclo 2.2.2!oct-3-ylidenecyanoacetic acid

A mixture of quinuclidinone hydrochloride (32 g, 0.2 mol) andcyanoacetic acid (20.2 g, 1.2 eq) in water (65 ml) was mechanicallystirred until a solution resulted. This was then cooled to approx 10° C.by immersion in an ice-water bath and sodium hydroxide pellets (27.0 g,3.4 eq) added portionwise with stirring over 1 h while maintaining thereaction temperature at 15°-25° C. with the aid of the ice-bath. Theresulting solution was then stirred at approx. 20° C. for an additional1.5 h after which time a thick suspension of the sodium salt of theproduct was deposited and the temperature of the mixture rose to 25° C.

Stirring was continued for another 1 h at room temperature before addingdropwise conc HCl (37 ml) over 0.5 h while maintaining the temperatureof the mixture at approx. 20° C. with external cooling. As the acid wasadded the suspension dissolved to give a near-solution before the freeacid of the product was deposited during the latter stages of theaddition. The final pH of the mixture was fine-adjusted to pH7 afterwhich stirring was continued for another 0.5 h and the mixture then leftto stand at room temperature for 48 h. It was then re-stirred whilechilling to 0°-5° C. for 3 h before filtering under suction. The filtercake was washed with a little ice-cold water and then dried, first undersuction and then under high vacuum at 40°-45° C. overnight Yield: 34.0 g(90%).

NMR (250 MHz, D₂ O) δ=2.02-2.17 (2H, m), 2.19-2.34 (2H, m), 3.30-3.57(SH, m), 4.61 (2H, s).

Stage 2 Preparation of α-cyano-1-azabicyclo 2.2.2!octane-3-acetic acid

The Stage 1 nitrile acid (20 g, 0.1 mol) was suspended in water (100 ml)and 5% Pd-C paste (type 87L, 61% moisture, 3.0 g) added. The mixture wasstirred vigorously under hydrogen at atmospheric pressure for 22 h. Itwas then filtered through celite under suction to give a solution of thereduced nitrile acid, the identity and purity of which was checked byNMR (D₂ O) of an evaporated aliquot. The solution of Stage 2 product wasused directly for the next stage.

NMR (250 MHz, D₂ O) δ=1.85-2.24 (4.35H, m), 2.30-2.36 (0.65H, m),2.63-2.80 (1H, m), 3.08-3.45 (5H, m) 3.56-3.77 (1H, m).

Stage 3 Preparation of title compound

The Stage 2 solution was chilled with stirring to 0°-5° C. using an icebath during which conc. HCl (19 ml, 0.24 mol) was also added over 1-2min. A solution of NaNO₂ (17 g, 0.25 mol) in water (230 ml) was thenadded dropwise over 1 h while maintaining the temperature at 0°-5° C. Aninitial very pale blue solution formed which turned greenish, whileevolution of gas (CO₂) also became quite apparent. After the additionwas complete the mixture was left to stir in the ice-bath while allowingto warm slowly to room temperature overnight. An NMR (D₂ O) of theresidue from a basified and evaporated aliquot showed an E:Z mixture(approx. 1:4 ratio) of the oxime to be present. The neutral reactionmixture was stirred and basified to pH8-9 by dropwise addition of asolution of NaOH (4.17 g, 0.1 mol) in water (6 ml), over 10 min duringwhich the zwitterionic Z-isomer of the product precipitated out. Thesuspension was stirred while chilling to 0°-5° C. for three hours, afterwhich it was left to stand at this temperature overnight beforefiltering under suction. The filter cake was washed with a littleice-cold water before drying under suction and then under high vacuum at40°-45° C. to afford the Example 1 title compound. Yield: 12.6 g (68%).

NMR (250 MHz, D₂ O) δ=1.82-2.15 (4H, m), 2.36-2.44 (1H, m), 3.20-3.43(SH, m), 3.50-3.65 (1H, m), 3.67-3.78 (1H, m).

The mother liquor from the filtration was acidified with conc. HCl (20ml) and then left to stand at room temperature for 18 h to convert thepredominantly E-isomer present into Z-isomer. Basification to pH 8-9with 40% aq. NaOH yielded a second crop of title compound which wassimilarly filtered off and dried. Yield: 2.2 g (12%).

Method B

Stage 1 Preparation of 1-azabicyclo 2.2.2!oct-3-ylidenecyanoacetic acid

40% Aqueous NaOH (370 ml, 3.7 mol) was added to a stirred suspension of3-quinuclidinone hydrochloride (600 g, 3.7 mol) in water (300 ml) over30 min while maintaining the temperature at 15°-25° C. The resultingmixture was then cooled to 15° C. and a solution of cyanoacetic acid(380 g, 4.5 mol) in water (150 ml) added in a steady stream over 30 minwhile stirring and maintaining the temperature at 15°-20° C. After theaddition was complete, further 40% aq. NaOH (900 ml, 9.0 mol) was addedgradually over 45 min while stirring and maintaining the temperature at15°-20° C. The resulting reddish solution was then left to stir atambient temperature for a further 2 h before cooling to 15° C. Seedingwith authentic sodium 1-azabicyclo 2.2.2!oct-3-ylidenecyanoacetateinduced crystallisation of the same, and the mixture was then chilledfurther to 7° C. with stirring until a thick slurry of the sodium saltwas obtained. After stirring at this temperature for a further 45 min amixture of conc HCl (725 ml) and water (725 ml) was added in a steadystream over 45 min while stirring and maintaining the temperature at15°-20° C. After adjusting to pH7 the resulting slurry of the Stage 1product was stirred at ambient temperature for an additional 45 minbefore using directly for Stage 2.

Stage 2 Preparation of α-cyano-1-azabicyclo 2.2.2!octane-3-acetic acid

10% Pd-C catalyst (type 487, dry powder, 66 g) was added to the slurryof the Stage 1 product and the mixture then stirred under hydrogen atatmospheric pressure for 65 h. It was then filtered through celite undersuction to give a solution of the Stage 2 product, the identity andpurity of which was checked by NMR (D₂ O) of an evaporated aliquot. Thesolution was used directly for the next stage.

Stage 3 Preparation of title compound

The Stage 2 solution was chilled with stirring to 7° C. and conc HCl(790 ml, 9.3 mol) added over 5 min. The stirred mixture was chilled backto 4° C. before adding a solution of NaNO₂ (360 g, 5.2 mol) in water(510 ml+60 ml washings) over 1 h while maintaining the temperature at4°-6° C. An initial very pale blue solution formed which turnedgreenish, while evolution of gas (CO₂) also became quite apparent. Afterthe addition was complete the mixture was left to stir at 4°-6° C. foran additional 2 h before allowing to warm slowly to room temperatureovernight. An NMR (D₂ O) of the residue from a neutralised andevaporated aliquot showed an E:Z mixture (˜1:5) of the oxime to bepresent together with a little unreacted 3-quinuclidinone (3-4%).

The reaction mixture was stirred and 40% aq. NaOH (390 ml, 3.9 mol)added in a steady stream over 1 h while maintaining the temperature at20°-25° C. During the addition the zwitterionic Z-oxime productprecipitated out. The addition of the 40% aq. NaOH was continued until afinal pH of 8-9 was obtained. The resulting suspension of Z-oxime wasthen chilled to 4°-5° C. with stirring and maintained at thistemperature for 2 h before filtering under suction. The filter cake waswashed with ice-cold water (600 ml) before leaving to suck dryovernight. The product was finally dried to constant weight at 50°-55°C. under high vacuum to afford the title compound. Yield: 455 g (68%from 3-quinuclidinone hydrochloride).

EXAMPLE 2 Preparation of R-(Z)!α-(oximino)-α-(1-azabicyclo2.2.2!oct-3-yl)acetonitrile

Stage 1

To a stirred suspension of racemic zwitterionicR,S-(Z)!-α-(oximino)-α-(1-azabicyclo 2.2.2!oct-3-yl)acetonitrile fromExample 1 (20.0 g, 0.11 mol) in water (148 ml) at 35° C. was added asolution of L(+) tartaric acid (16.8 g, 0.11 mol) in water (100 ml) at30° C. The resultant mixture was warmed to 50° C., giving a homogenoussolution which was then stirred at ambient temperature for 20 h. Thecrystalline product was filtered off, washed with water (20 ml) thensucked dry on the filter.

Stage 2

The damp solid from Stage 1 was slurried with water (49 ml) and heatedto 95° C., giving a homogenous solution. This solution was stirred atambient temperature, and seed crystals of authenticR-(Z)!-α-(oximino)-α-(1-azabicyclo 2.2.2!oct-3-yl)acetonitrileL-(+)-tartrate salt were added at intervals until crystallisationoccurred. Stirring was continued at ambient temperature for 16 h. Thecrystalline product was filtered off, washed with water (8 ml) thensucked dry to give the tartrate salt in high enantiomeric purity(e.e.>99%), (2.5 g, 68%).

NMR (250 MHz, DMSO) δ=1.65 (2H, m), 1.85 (2H, m), 2.22 (1H, m),2.95-3.20 (5H, m), 3.35 (2H, d, J=7 Hz), 4.05 (2H, s).

Stage 3

A slurry of R-(Z)!-α-(oximino)-α-(1-azabicyclo2.2.2!oct-3-yl)acetonitrile L-(+)-tartrate salt from Stage 2 (12.5 g, 38mmol) in water (60 ml) was stirred and heated to 95° C., giving ahomogenous solution. Aqueous sodium hydroxide (10M) was added to thissolution in 0.5 ml portions. A graph of solution pH ν volume of baseadded was plotted, and the end point for base addition was determined asthe second rapid pH change. A total of 7.5 ml of base was added. Themixture was cooled to 0° C., then stirred at this temperature for 1.5 h.The crystalline solid was filtered off, washed with a small volume ofcold water, then dried in vacuo at 60° C. to give the title compound(6.3 g, 93%) of high enantiomeric purity (e.e. >99.8%).

NMR (400 MHz, DMSO) δ=1.38 (1H, m), 1.48 (1H, m), 1.60 (2H, m), 2.00(1H, m), 2.65-2.75 (5H, m), 2.90-3.05 (2H, m), 13.10 (1H, s, br).

EXAMPLE 3 Preparation of R,S-(Z)!-α-(methoxyimino)-α-(1-azabicyclo2.2.2!oct-3-yl)acetonitrile

Zwitterionic R,S-(Z)!-α-(oximino)-α-(1-azabicyclo2.2.2!oct-3-yl)acetonitrile from Example 1 (35.1 g, 196 mmol) wassuspended in a mixture of DMSO (250 ml) and THF (175 ml) and stirredunder nitrogen while cooling to 10° C. Potassium tert-butoxide (21.9 g,195 mmol) was added in one lot and stirring continued for approx. 0.5 huntil a yellow solution resulted. The temperature rose to reach 15° C.before dropping back with external cooling. The temperature of thesolution was brought down to -1° C. using an acetone/CO₂ bath before asolution of methyl tosylate (36.0 g, 194 mmol) in THF (75 ml) was addeddropwise over 45 min while maintaining the reaction temperature at 0°-2°C. The mixture was stirred for an additional 0.5 h at 0°-5° C. by whichtime a thick yellow suspension had formed. Ice-cold water (100 ml) wasadded and the resulting solution transferred to a separating funnelcontaining further water (100 ml). The mixture was extracted with EtOAc(200 ml+5×130 ml portions) and the combined extracts washed with water(3×40 ml) and then brine (20 ml+40 ml) before drying over Na₂ SO₄.Evaporation afforded the title compound as a mobile yellow oil, 91 %pure by HPLC relative assay. Yield: 29.4 g (78%).

NMR (250 MHz, CDCl₃) δ=1.40-1.55 (1H, m), 1.58-1.80 (3H, m), 2.07-2.20(1H, m), 2.60-3.14 (6H, m), 3.20-3.34 (1H, m), 4.08 (3H, s).

EXAMPLE 4 Preparation of R-(Z)!-α-(methoxyimino)-α-(1-azabicyclo2.2.2!oct-3-yl)acetonitrile.

Method A

Resolution of R,S-(Z)!-α-(methoxyimino)-α-(1-azabicyclo2.2.2!oct-3-yl)acetonitrile.

To a solution of R,S-(Z)!-α-(methoxyimino)-α-(1-azabicyclo2.2.2!oct-3-yl)acetonitrile from Example 3 (105.3 mg, 0.55 mmol) inethanol (0.1 ml) was added a solution of2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid monohydrate (79.7 mg,0.27 mmol) in ethanol (0.5 ml). The resultant solution was stirred atambient temperature, then allowed to stand for 16 h. The crystallineproduct was filtered off, washed with a small volume of cold ethanolthen dried in vacuo at 60° C. to give the title compound as its2,3:4,6-di-O-isopropylidene 2-keto-L-gulonate salt, (44.5 mg, 34%) inhigh enantiomeric purity (e.e.>97%).

NMR (250 MHz, DMSO) δ=1.20 (3H, s), 1.32 (3H, s), 1.38 (3H, s), 1.40(3H, s), 1.60 (2H, m), 1.78 (2H, m), 2.16 (1H, m), 2.75-3.15 (5H, m),3.20 (2H, m), 3.85 (1H, m), 3.95-4.10 (2H, m), 4.05 (3H, s), 4.20 (1H,m), 4.66 (1H, s).

Method B

Resolution of E/Z mixture of R,S!-α-(methoxyimino)-α-(1-azabicyclo2.2.2!oct-3yl)acetonitrile

Stage 1

A solution of R,S-(E,Z)!-α-(methoxyimino)-α-(1-azabicyclo2.2.2!oct-3-yl)acetonitrile (41 g) was dissolved in ethyl acetate (100ml) and a solution of 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acidmonohydrate (22.5 g, 0.077 mol) in ethyl acetate (400 ml) was added.Crystallisation occurred whilst standing for 16 hours. The crystals wereisolated by filtration to give the2,3:4,6-di-O-isopropylidene-2-keto-L-gulonate salt (19.3 g, 0.041 mol,54%).

Stage 2

A solution of R,S-(E,Z)!-α-(methoxyimino)-α-(1-azabicyclo2.2.2!oct-3-yl)acetonitrile in ethyl acetate (the mother liquors fromthe crystallisation in Stage 1), was washed with 5% aqueous potassiumcarbonate solution, then washed with saturated aqueous potassiumcarbonate solution and concentrated. The residue was dissolved in THF(ca 30 wt % solution), and potassium tert-butoxide (5 wt %) was added.After 1 hour the reaction was partitioned between ethyl acetate and 5%aqueous potassium carbonate solution. The organic phase was separated,washed (5%aq K₂ CO₃), dried, filtered through silica and concentrated togive a racemic mixture.

The racemic mixture was used as a starting material for a resolution inaccordance with Stage 1.

EXAMPLE 5 Preparation of R-(Z)!-α-(methoxyimino)-α-(1-azabicyclo2.2.2!oct-3-yl)acetonitrile monohydrochloride

Method A

Stage 1--Isolation of title compound as free base

The salt from Example 4, Method B, Stage 1 (86 g) was dissolved in water(400 ml) and the solution made basic with saturated aqueous potassiumcarbonate. The solution was extracted with ethyl acetate (500 ml) andthe extract washed with 5% aqueous potassium carbonate (2×100 ml) thensaturated aqueous potassium carbonate (2×20 ml). The combined aqueousphases were extracted with a further 400 ml of ethyl acetate and theextract washed as above. The combined ethyl acetate extracts were driedover potassium carbonate and concentrated to give the free base (38 g).

Stage 2--Salt formation (title compound)

The free base from Stage 1 (63 g; 0.33 mol) was dissolved in isopropylalcohol (500 ml) and concentrated hydrochloric acid (28 ml, 0.33 mol)was added. The mixture was diluted with ethyl acetate (11) and the solidcollected by filtration, washed with ethyl acetate (2×100 ml) and driedat ambient temperature under reduced pressure (1 mm Hg) for 4 hours togive the title compound (43.9 g).

A second crop was obtained by concentrating the mother liquor to ˜250 mland adding ethyl acetate (500 ml). This was washed and dried as above(14.3 g).

Method B

Zwitterionic R-(Z)!-α-(oximino)-α-(1-azabicyclo2.2.2!oct-3-yl)acetonitrile from Example 2 (6.0 g, 34 mmol) wassuspended in a mixture of DMSO (42 ml) and THF (12 ml) and stirred undernitrogen whilst cooling to 7° C. Potassium tert-butoxide (3.76 g, 33mmol) was added in one portion. The cooling bath was removed andstirring was continued for 15 min during which time a homogenoussolution formed and the temperature rose to 13° C. This solution wascooled to 7° C., then a solution of methyl tosylate (6.84 g, 37 mmol) inTHF (6 ml) was added dropwise whilst maintaining the reaction mixturetemperature at ≦13° C. The resultant mixture was stirred at ambienttemperature for 2 h, then aqueous potassium carbonate (0.2M, 30 ml) wasadded in one portion. The temperature rose to ca. 40° C., then wasfurther raised to 55°-60° C. and maintained at this temperature for 2 h.The resultant solution was extracted with ethyl acetate (3×30 ml), andthe combined extracts were washed with aqueous potassium carbonate(0.2M, 18 ml) and water (18 ml). Propan-2-ol (100 ml) was added and thesolution evaporated to a volume of 10-20 ml. Additional propan-2-ol (60ml) was then added and the solution again evaporated to a volume of10-20 ml. The volume was increased to 27 ml by the addition ofpropan-2-ol and the solution cooled to 5° C. Concentrated hydrochloricacid (2.0 ml, 24 mmol) was added slowly with stirring, keeping thetemperature below 12° C. This mixture was stirred for 15 min, then ethylacetate (60 ml) was added portionwise. The mixture was stored at 4° C.for 16 h, then the crystalline solid was filtered off, washed with asmall volume of ethyl acetate then dried in vacuo at 30° C. to give thetitle compound (3.1 g, 40%).

NMR (250 MHz, DMSO) δ=1.75 (2H, m), 1.95 (2H, m), 2.33 (1H, m),3.05-3.28 (4H, m), 3.28-3.55 (3H, m), 4.08 (3H, s), 11.12 (1H, s, br).

    ______________________________________                                        DMSO              dimethyl sulphoxide                                         THF               tetrahydrofuran                                             EtOAc             ethyl acetate                                               ______________________________________                                    

We claim:
 1. A process for separating the Z formof--(oximino)--(1-azabicyclo 2.2.2!oct-3-yl)acetonitrile from thecorresponding E isomer by precipating out from a solution mixture of theE and Z isomer by addition of base to a pH of about 8 to about 9.